PROJECT SUMMARY Signal transduction is a universal biological process vital to all organisms. Due to their central role in disease, signal transduction systems in humans and in bacterial pathogens are the primary targets of drug design. Our long-term goal is to understand how cells detect, transmit, and adapt to signals. The main focus of this project is on the bacterial chemotaxis system, which is the best studied model for understanding fundamentals of signal transduction at the molecular level and also an important determinant of virulence in many pathogenic bacteria. The main unanswered questions that we propose to address are: (1) which small molecule ligands are recognized by bacteria, (2) how these signals are transmitted from chemoreceptors to a dedicated kinase, and 3) what are the determinants of receptor/kinase specificity. We propose to build on our previous findings and capitalize on our tool development to obtain this knowledge in collaboration with several experimental laboratories and to capture this knowledge as predictive models. These models will be stored in public databases, such as Pfam and our own MiST (Microbial Signal Transduction) database. Current MiST capabilities will be enhanced with new search and download options and updated with a vast amount of sequences from the Human Microbiome Project and other metagenomics datasets, resulting in a resource that can better serve an even greater scientific community. Finally, we will extend our evolutionary analyses to the key eukaryotic signal transduction pathway, where we aim at predicting consequences of missense mutations in the context of developmental disorders and cancer.